1. Field of the Invention.
This invention relates to the preparation of piperazine derivatives and more particularly pertains to an improved process for preparing 1-methylpiperazine and 1,4-dimethylpiperazine as co-products free from piperazine impurity. 1-methylpiperazine and 1,4-dimethylpiperazine have utility as curing agents for resins, as intermediates for drugs, and in the synthesis of dyes and derivatives having pharmacological utility.
2. Description of the Prior Art.
Processes for the preparation of 1-methylpiperazine and 1,4-dimethylpiperazine by the catalytic hydrogenation of the reaction product of formaldehyde and piperazine are well-known in the art. Generally, such procedures include mixing and reacting formaldehyde and piperazine in an aqueous medium at a molar ratio between 1:1 to 2:1 formaldehyde:piperazine and then hydrogenating the crude reaction product carried in a liquid solvent in the presence of a hydrogenation catalyst under mild hydrogenation conditions. 1-methylpiperazine and 1,4-dimethylpiperazine can be separated in good yields from the hydrogenated crude reaction product. Baltzly et al (Journal American Chemical Society, 66 (1944), pp. 63-66) and Prelog and Stepan (Coll.Trav.Chim.Tchecosl. 7, (1935), pp. 93-102) disclose procedures for the preparation of the above-mentioned mono- and di-alkylated piperazines. More particularly, U.S. Pat. No. 2,639,284 to Morren, discloses the preparation of 1-methylpiperazine by the process of mixing and reacting piperazine hexahydrate and 34.5% aqueous formaldehyde, in a piperazine:formaldehyde molar ratio of 1:1 in butanol or ethanol solvent and then catalytically hydrogenating the reaction mixture under mild conditions resulting in a product high in 1-methylpiperazine which also contains substantial amounts of 1,4-dimethylpiperazine and piperazine. W. T. Forsee, Jr. and C. B. Pollard, J.Am.Chem. Soc. 57, 1788 ( 1935), describe the formation of an 88% yield of 1,4-dimethylpiperazine from the reaction of piperazine and aqueous formaldehyde (1:2 molar ratio of piperazine:formaldehyde) with subsequent treatment with hydrogen generated by zinc and hydrochloric acid. German Pat. No. 1,932,422 (1971) discloses admixing formaldehyde, water, piperazine and isobutanol as solvent and then hydrogenating the reaction mixture to provide 90.5% methylpiperazine upon distillation of the hydrogenated product. French Pat. No. 1,592,964 describes a process whereby an aqueous solution of pg,3 piperazine (60 wt.% piperazine) and 30% aqueous formaldehyde are mixed and reacted in the presence of piperazine acetate with subsequent hydrogenation of the reaction mixture to provide a reaction product containing 99.3% methylpiperazine and piperazine.
Although 1-methylpiperazine and/or 1,4-dimethylpiperazine can be produced in high yields by any of the aforementioned processes by adjusting the molar ratio of piperazine:formaldehyde, these known processes have suffered from the disadvantage of producing crude hydrogenated reaction products containing piperazine as an impurity, either as unreacted product or as a by-product. The separation of substantially pure 1-methylpiperazine from such crude reaction products containing piperazine has been found to be most difficult, if not impossible, as a practical matter. The presence of piperazine as an impurity in 1-methylpiperazine limits the utility of 1-methylpiperazine, particularly in the pharmacological industry for the preparation of certain drugs. Piperazine is also reactive and can form other undesirable derivative impurities. In fact, 1-methylpiperazine containing as little as 0.1wt.% piperazine cannot be employed in the manufacture of many drug derivatives for human and/or animal use.
Even recognizing the difficulties in separating essentially pure 1-methylpiperazine and/or 1,4-dimethylpiperazine from admixture with piperazine, it has heretofore been the common practice in the industry to prepare such products by the above-mentioned processes employing formaldehyde and piperazine feeds in conjunction with extensive separation techniques. For example, U.S. Pat. No. 2,639,284 teaches the addition of carbon disulfide to the hydrogenated formaldehyde-piperazine reaction product mixture and subsequent treatment with concentrated hydrochloric acid with reflux for the preparation of the desired 1-methylpiperazine. U.S. Pat. No. 2,919,275 discloses the separation of 1-methylpiperazine by selective precipitation of the diacetate derivative from which the 1-methylpiperazine can be regenerated through caustic hydrolysis. U.S. Pat. No. 3,069,331 teaches a process for the separation of piperazine and 1-methylpiperazine by extensive extractive distillation of the mixture in the presence of a countercurrent flow of ethylene glycol.
Although some of the aforementioned procedures have apparently been successful to some extent in the preparation of substantially pure 1-methylpiperazine and/or 1,4-dimethylpiperazine products, they all involve extensive reaction procedures and/or extensive treatment of the hydrogenated crude reaction products which inherently adversely affect the economics of the preparation of the desired product.
Surprisingly, I have now found that 1-methylpiperazine and 1,4-dimethylpiperazine can be prepared from formaldehyde and piperazine as co-products in a crude reaction product mixture which contains no free piperazine as an impurity. It is believed that my invention is a tremendous advance in the art of preparing such products in essentially pure form. Most unexpectedly, I have discovered that the molar ratio of piperazine:formaldehyde employed, the particular liquid solvent employed, and the particular amount of water present during the hydrogenation of the crude reaction product of piperazine and formaldehyde affect the presence of piperazine in the crude hydrogenated reaction product. Through the practice of my invention, 1-methylpiperazine and/or 1,4-dimethylpiperazine can be produced in essentially pure form without the requirement of subjecting the product to the aforementioned extensive procedures for separating piperazine impurity. Essentially pure 1-methylpiperazine and 1,4-dimethylpiperazine products can be obtained in the practice of my invention by relatively simple, well-known distillation techniques.